VCV000011548.17 - ClinVar

NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (3); Likely pathogenic (1)

4 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)

Variation ID: 11548 Accession: VCV000011548.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq26.3 X: 136208625 (GRCh38) [ NCBI UCSC ] X: 135290784 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Feb 15, 2026	Jan 27, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_001159699.2:c.720C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001153171.1:p.Cys240Trp	missense
NM_001159702.3:c.672C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001153174.1:p.Cys224Trp	missense
NM_001159700.2:c.672C>G	NP_001153172.1:p.Cys224Trp	missense
NM_001159701.2:c.759C>G	NP_001153173.1:p.Cys253Trp	missense
NM_001159703.2:c.501+664C>G		intron variant
NM_001159704.1:c.672C>G	NP_001153176.1:p.Cys224Trp	missense
NM_001167819.1:c.672C>G	NP_001161291.1:p.Cys224Trp	missense
NM_001330659.2:c.549+664C>G		intron variant
NM_001369326.1:c.672C>G	NP_001356255.1:p.Cys224Trp	missense
NM_001369327.2:c.672C>G	NP_001356256.1:p.Cys224Trp	missense
NM_001369328.1:c.672C>G	NP_001356257.1:p.Cys224Trp	missense
NM_001369329.1:c.672C>G	NP_001356258.1:p.Cys224Trp	missense
NM_001369330.1:c.672C>G	NP_001356259.1:p.Cys224Trp	missense
NM_001369331.1:c.672C>G	NP_001356260.1:p.Cys224Trp	missense
NM_001449.5:c.672C>G	NP_001440.2:p.Cys224Trp	missense
NR_027621.2:n.1083C>G		non-coding transcript variant
NC_000023.11:g.136208625C>G
NC_000023.10:g.135290784C>G
NG_015895.1:g.66226C>G
LRG_739:g.66226C>G
LRG_739t1:c.720C>G	LRG_739p1:p.Cys240Trp
LRG_739t2:c.672C>G	LRG_739p2:p.Cys224Trp
	Q13642:p.Cys224Trp

... more HGVS ... less HGVS

Protein change

C224W, C240W, C253W

Other names

Canonical SPDI

NC_000023.11:136208624:C:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA255927 UniProtKB: Q13642#VAR_042605 OMIM: 300163.0002 dbSNP: rs122458141 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FHL1		-	-	GRCh38 GRCh37	676	861

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
X-linked myopathy with postural muscle atrophy	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 27, 2026	RCV000012304.41
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 3, 2025	RCV000725941.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 27, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	X-linked myopathy with postural muscle atrophy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001588249.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 18179888‚ 19687455‚ 22923418‚ 24634512 Comment: show This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the FHL1 protein (p.Cys224Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myopathy with postural muscle atrophy and generalized hypertrophy (PMID: 18179888, 19687455, 22923418). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11548). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FHL1 function (PMID: 24634512). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 23, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000340671.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FHL1 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Hemizygote Sex: mixed

Pathogenic (Jun 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV007333581.1 First in ClinVar: Jan 24, 2026 Last updated: Jan 24, 2026	Comment: show The FHL1 c.672C>G; p.Cys224Trp variant (rs122458141, ClinVar Variation ID: 11548 ) is reported in the literature in individuals affected with X-linked postural muscle atrophy (XMPMA) and generalized hypertrophy (Binder 2012, Feldkirchner 2013, Schoser 2009). Additionally, this variant was found to segregate with disease in an X-linked recessive manner consistent with XMPMA in six individuals in a single family (Windpassinger 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.798). In vitro functional analyses in C2C12 cells demonstrate similar expression to wildtype FHL1 but showed impaired differentiation (Wilding 2014), additionally patient muscle biopsy showed a marked decrease in protein expression of FHL1 (Windpassinger 2008). Based on available information, this variant is considered to be pathogenic. References: Binder JS et al. Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet. 2012 Oct 1;5(5):490-502. PMID: 22923418. Feldkirchner S et al. Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy. Neuromuscul Disord. 2013 May;23(5):418-26. PMID: 23489660. Schoser B et al. Consequences of mutations within the C terminus of the FHL1 gene. Neurology. 2009 Aug 18;73(7):543-51. PMID: 19687455. Wilding BR et al. FHL1 mutants that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation. J Cell Sci. 2014 May 15;127(Pt 10):2269-81. PMID: 24634512. Windpassinger C et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. 2008 Jan;82(1):88-99. PMID: 18179888. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Jan 01, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	X-linked myopathy with postural muscle atrophy	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440683.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Aug 18, 2009) N Not contributing to aggregate classification	no assertion criteria provided	MYOPATHY, X-LINKED, WITH POSTURAL MUSCLE ATROPHY	OMIM Accession: SCV000032538.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (2) PubMed: 18179888‚ 19687455 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In an extensive Austrian family in which males in 5 generations had a novel form of myopathy referred to as X-linked myopathy with postural muscle … (more) In an extensive Austrian family in which males in 5 generations had a novel form of myopathy referred to as X-linked myopathy with postural muscle atrophy and generalized hypertrophy (XMPMA; 300696), Windpassinger et al. (2008) detected a 672C-G transversion in the FHL1 gene that resulted in a cys224-to-trp (C224W) substitution in the fourth LIM domain of isoform A and in the nuclear localization signal of isoform B. Patients had muscle hypertrophy in the early stages, followed by postural muscle weakness and atrophy, increased serum creatine kinase, bent spine, and cardiomyopathy. The C224W mutation was predicted to disrupt the zinc-binding properties of FHL1A and to impair shuttling between nucleus and cytoplasm of FHL1B. Impairment of zinc binding may have reduced protein stability and structure. Isoform C was not affected, which the authors hypothesized may have resulted in the relatively mild phenotype; no females were affected. Schoser et al. (2009) reported 3 additional unrelated German families with XMPMA associated with the C224W mutation in the FHL1 gene. A fourth patient, later found to be distantly related to the Austrian family reported by Windpassinger et al. (2008), was also identified. The phenotype was similar to that reported by Windpassinger et al. (2008). The mutation is predicted to disrupt the fourth LIM domain. (less)

Pathogenic (Jun 11, 2024) N Not contributing to aggregate classification	no assertion criteria provided	X-linked myopathy with postural muscle atrophy	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV006323808.1 First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the FHL1 protein (p.Cys224Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myopathy with postural muscle atrophy and generalized hypertrophy (PMID: 18179888, 19687455, 22923418). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11548). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FHL1 function (PMID: 24634512). For these reasons, this variant has been classified as Pathogenic.

Comment:

The FHL1 c.672C>G; p.Cys224Trp variant (rs122458141, ClinVar Variation ID: 11548 ) is reported in the literature in individuals affected with X-linked postural muscle atrophy (XMPMA) and generalized hypertrophy (Binder 2012, Feldkirchner 2013, Schoser 2009). Additionally, this variant was found to segregate with disease in an X-linked recessive manner consistent with XMPMA in six individuals in a single family (Windpassinger 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.798). In vitro functional analyses in C2C12 cells demonstrate similar expression to wildtype FHL1 but showed impaired differentiation (Wilding 2014), additionally patient muscle biopsy showed a marked decrease in protein expression of FHL1 (Windpassinger 2008). Based on available information, this variant is considered to be pathogenic. References: Binder JS et al. Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet. 2012 Oct 1;5(5):490-502. PMID: 22923418. Feldkirchner S et al. Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy. Neuromuscul Disord. 2013 May;23(5):418-26. PMID: 23489660. Schoser B et al. Consequences of mutations within the C terminus of the FHL1 gene. Neurology. 2009 Aug 18;73(7):543-51. PMID: 19687455. Wilding BR et al. FHL1 mutants that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation. J Cell Sci. 2014 May 15;127(Pt 10):2269-81. PMID: 24634512. Windpassinger C et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. 2008 Jan;82(1):88-99. PMID: 18179888.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
FHL1 mutants that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation.	Wilding BR	Journal of cell science	2014	PMID: 24634512
Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and-a-half LIM domain 1 gene.	Binder JS	Circulation. Cardiovascular genetics	2012	PMID: 22923418
Consequences of mutations within the C terminus of the FHL1 gene.	Schoser B	Neurology	2009	PMID: 19687455
An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1.	Windpassinger C	American journal of human genetics	2008	PMID: 18179888
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FHL1	-	-	-	-

Text-mined citations for rs122458141 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026